Nalmefene salts as medicaments for reducing alcohol consumption or for preventing excessive alcohol consumption

ABSTRACT

The present invention relates to new nalmefene salts which salts fall within at least one of the two following categories: non-hydrate forming salts and non-solvate forming salts. In particular, the invention relates to the hydrogen adipate salt, the hydrogen malonate salt, the lactate salt, the hydrogen fumarate salt, the hydrogen succinate salt, the benzene sulfonate salt, the hydrogen maleate salt and the salicylate salt of nalmefene. The present invention also relates to such salts for use in therapy.

CROSS REFERENCE TO RELATED APPLICATIONS AND CLAIM TO PRIORITY

The present application is a §371 National Stage Application ofPCT/EP2014/064819 (filed on Jul. 10, 2014; pending), which applicationclaims priority to Denmark Patent Application No. PA201300421 (filed onJul. 11, 2013), each of which applications is herein incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to new nalmefene salts which salts fallwithin at least one of the two following categories: non-hydrate formingsalts and non-solvate forming salts. In particular, the inventionrelates to the hydrogen adipate salt, the hydrogen malonate salt, thelactate salt, the hydrogen fumarate salt, the hydrogen succinate salt,the benzene sulfonate salt, the hydrogen maleate salt and the salicylatesalt of nalmefene. The present invention also relates to such salts foruse in therapy.

BACKGROUND OF THE INVENTION

Nalmefene[17-(cyclopropylmethyl)-4,5-alpha-epoxy-6-methylenemorphinan-3,14-diol]has the following general formula:

and can be prepared using methods that are well known in the art e.g.starting by manufacturing of naltrexone from noroxymorphone as describedin WO 2012/059103 and subsequently manufacturing nalmefene fromnaltrexone e.g. by the Wittig reaction as described in WO 2010/136039.

Nalmefene is an opioid system modulator with a distinct μ, δ, and κreceptor profile. In vitro studies have demonstrated that nalmefene is aselective opioid receptor ligand with antagonist activity at the μ and δreceptors and partial agonist activity at the κ receptor. Acute alcoholintake was shown to result in mesolimbic dopamine release (facilitatedby the release of β-endorphins), which can provide positivereinforcement. Nalmefene is thought to counteract the reinforcementeffects and to reduce alcohol consumption, possibly by modulating thesecortico-mesolimbic functions.

The efficacy and tolerability of nalmefene in the treatment of alcoholdependence have been evaluated in three phase III studies (twoconfirmatory 6-month efficacy studies and one 1-year safety study)conducted by Lundbeck (Mann et al. Extending the Treatment Options inAlcohol Dependence: A Randomized Controlled Study of As-NeededNalmefene. Biol Psychiatry (2013); 73(8): 706-713; Gual et al. Arandomised, double-blind, placebo-controlled, efficacy study ofnalmefene, as-needed use, in patients with alcohol dependence. EuropeanNeuropsychopharmacology (2013); 23(11): 1432-1442; van den Brink et al.,Long-term efficacy, tolerability and safety of nalmefene as-needed inpatients with alcohol dependence: A 1-year, randomised controlled study.J. Psychopharmacol., published online before print Mar. 26, 2014, doi:10.1177/0269881114527362) and 5 studies in alcohol use disordersconducted by the company Biotie (Karhuvaara et al. Alcohol. Clin ExpRes. (2007); 31: 1179-1187).

A marketing authorization was granted in February 2013 in the EuropeanUnion (EU) for oral nalmefene under the tradename Selincro® for thereduction of alcohol consumption in adult patients with alcoholdependence.

The only known salt of nalmefene is the hydrochloride salt. Saidnalmefene hydrochloride salt has been described as a hydrate-formingsalt and known forms are nalmefene hydrochloride monohydrate (Brittain,H. G., Analytical Profiles of Drug Substances and Excipients; 1996, Vol.24: 351-395) and nalmefene hydrochloride dihydrate (WO 2010/063292).Methods for obtaining said nalmefene hydrochloride monohydrate anddihydrate from crude nalmefene hydrochloride are described in WO2010/063292.

It has not been possible to obtain a stable anhydrous form of Nalmefenehydrochloride as formation of anhydrous material by dehydration of ahydrate lead to hygroscopic material that absorbs water undertransformation to a hydrate, and crystallization from ethanol lead toethanol solvate (Brittain, H. G., Analytical Profiles of Drug Substancesand Excipients; 1996, Vol. 24: 351-395 and WO 2010/063292).

There is a need for new salts of nalmefene with improved properties e.g.for chemical processing and for pharmaceutical formulation and storage.

SUMMARY OF THE INVENTION

The invention provides new nalmefene salts which possess at least one ofthe following properties: non-solvate forming and non-hydrate forming.

The present invention relates to a salt of the compound of formula [I]

wherein said salt falls within at least one of the two followingcategories:

-   a) non-hydrate forming salt;-   b) non-solvate forming salt.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising a salt of the present invention.

In one embodiment, the invention relates to a salt of the presentinvention for use in therapy.

In one embodiment, the invention relates to a salt of the presentinvention for use in reduction of alcohol consumption in a patient withalcohol dependence.

BRIEF DESCRIPTION OF DRAWINGS

X-ray powder diffractograms (XRPDs) according to FIGS. 1-8 are obtainedusing CuK_(α1) radiation (λ=1.5406 Å). The y-axis shows the intensity(counts) and the x-axis shows the 2θ-angles (°).

FIG. 1: XRPD pattern of the hydrogen adipate salt of nalmefene.

FIG. 2: XRPD pattern of the hydrogen malonate salt of nalmefene.

FIG. 3: XRPD pattern of the L-lactate salt of nalmefene.

FIG. 4: XRPD pattern of the hydrogen fumarate salt of nalmefene.

FIG. 5: XRPD pattern of the hydrogen succinate salt of nalmefene.

FIG. 6: XRPD pattern of the benzene sulfonate salt of nalmefene.

FIG. 7: XRPD pattern of the hydrogen maleate salt of nalmefene.

FIG. 8: XRPD pattern of the salicylate salt of nalmefene. TGA and DSCprofiles of nalmefene salts are shown in FIGS. 9-16. The X axis showsthe temperature (° C.), the left hand y-axis shows the TGA weight loss(%), the right hand y-axis shows the DSC heat flow (W/g).

FIG. 9: TGA and DSC thermograms of the hydrogen adipate salt ofnalmefene.

FIG. 10: TGA and DSC thermograms of the hydrogen malonate salt ofnalmefene.

FIG. 11: TGA and DSC thermograms of the L-lactate salt of nalmefene.

FIG. 12: TGA and DSC thermograms of the hydrogen fumarate salt ofnalmefene.

FIG. 13: TGA and DSC thermograms of the hydrogen succinate salt ofnalmefene.

FIG. 14: TGA and DSC thermograms of the benzene sulfonate salt ofnalmefene.

FIG. 15: TGA and DSC thermograms of the hydrogen maleate salt ofnalmefene.

FIG. 16: TGA and DSC thermograms of the salicylate salt of nalmefene.

FIG. 17: Table with structural formulas of [a]: adipic acid, [b]:malonic acid, [c]: lactic acid, [d]: fumaric acid, [e]: succinic acid,[f]: benzene sulfonic acid, [g]: maleic acid, [h]: salicylic acid.

DEFINITIONS

In the present context, a “non-solvate forming salt” of Nalmefeneindicates a salt that generally does not form solvates when precipitatedfrom various organic solvents e.g. EtOH, MeOH, IPA, EtOAc, acetone, ACN,THF, MIBK, toluene and 2,2,2-trifluoroethanol. In particular, said saltsare non-solvate forming when solvent molecules do not form part of thecrystal lattice of the salts precipitated from different solvents atatmospheric pressure and room temperature such as in a temperature rangebetween 15-30° C., such as between 20-25° C. A “solvate” indicates acrystalline material with solvent molecules incorporated into thecrystal lattice. In the present context, when referring to “solvents”these are limited to non-aqueous solvents, preferably organic solvents.Solvents assessed for solvate formation according to the inventionincludes the following: ethanol (EtOH), methanol (MeOH), isopropanol(IPA), ethyl acetate (EtOAc), acetone, acetonitrile (ACN),tetrahydrofurane (THF), methyl isobutyl ketone (MIBK), toluene and2,2,2-trifluoroethanol.

In the present context, a “non-hydrate forming salt” of nalmefeneindicates a salt that does not form a hydrate when precipitated from anaqueous solution such as water. In particular, said salts arenon-hydrate forming when water molecules do not form part of the crystallattice of the salt precipitated from water at atmospheric pressure androom temperature such as in a temperature range between 15-30° C., suchas between 20-25° C. A “hydrate” indicates a crystalline material withwater (H₂O) molecules incorporated into the crystal lattice. Moreparticularly, a “non-hydrate forming salt” of nalmefene indicates a saltof which any isolated crystal form contains less than 25 mol % water,such as less than 20 mol % water, such as less than 15 mol % water, suchas less than 10 mol % water, such as less than 5 mol % water, such asless than 4, 3, 2 or 1 mol % water, such as substantially no water inthe crystal lattice of said salt.

In the present context, an “aqueous solution” is a solution comprisingan essential amount of water such as a solution comprising at least 50%water, such as at least 60, 70, 80 or 90% water, such as at least 95 or99% water, such as a solution comprising pure water.

Throughout the application “salts of the present invention” or“nalmefene salts of the present invention” indicates a nalmefene salt,which salt falls within at least one of the two following categories: a)non-hydrate forming salt; b) non-solvate forming salt. The salts of thepresent invention are all acid addition salts of acids that arepharmaceutically acceptable.

In the present context, “1:1 salt” indicates a salt comprising 1 eq ofthe compound of formula [I] and 0.8-1.2 eq of a saltforming acid, suchas 1 eq of the compound of formula [I] and 0.9-1.1 eq of a saltformingacid, such as 1 eq of the compound of formula [I] and 0.95-1.05 eq of asaltforming acid, such as 1 eq of the compound of formula [I] and0.98-1.02 eq of a saltforming acid. In one embodiment, “1:1 salt”indicates a salt comprising 1 eq of the compound of formula [I] and 1 eqof a saltforming acid.

In the present context, “hydrogen adipate” salt of nalmefene refers tothe 1:1 salt of the compound of formula [I] and adipic acid.

In the present context, “hydrogen malonate” salt of nalmefene refers tothe 1:1 salt of the compound of formula [I] and malonic acid.

In the present context, “lactate” salt of nalmefene refers to the 1:1salt of the compound of formula [I] and lactic acid. In particular,“DL-lactate” salt of nalmefene refers to the 1:1 salt of the compound offormula [I] and DL-lactic acid. In particular, “D-lactate” salt ofnalmefene refers to the 1:1 salt of the compound of formula [I] andD-lactic acid. In particular, “L-lactate” salt of nalmefene refers tothe 1:1 salt of the compound of formula [I] and L-lactic acid.

In the present context, “hydrogen fumarate” salt of nalmefene refers tothe 1:1 salt of the compound of formula [I] and fumaric acid.

In the present context, “hydrogen succinate” salt of nalmefene refers tothe 1:1 salt of the compound of formula [I] and succinic acid.

In the present context, “benzene sulfonate” salt of nalmefene refers tothe 1:1 salt of the compound of formula [I] and benzene sulfonic acid.

In the present context, “hydrogen maleate” salt of nalmefene refers tothe 1:1 salt of the compound of formula [I] and maleic acid.

In the present context, “salicylate” salt of nalmefene refers to the 1:1salt of the compound of formula [I] and salicylic acid.

In the present context, by expressions like “crystalline form of aspecific salt of nalmefene characterized by the XRPD shown in FIG. 1” ismeant the crystalline form of a salt of nalmefene having an XRPDsubstantially similar to FIG. 1, i.e. exhibiting an XRPD pattern withreflections substantially at the angles as exemplified in that Figureand measured under comparable conditions as described herein or by anycomparable method.

In the present context, “Pharmaceutical composition” refers to a soliddose form, such as a solid oral dose form, typically tablets orcapsules. “Pharmaceutical compositions of the present invention” refersto all pharmaceutical compositions covered by the claims anddescription.

In the present context, a “unit dosage form” refers to a formulationunit of a pharmaceutical composition e.g. one tablet or capsule.

In the present context, “therapeutically effective amount” of nalmefenemeans the amount/dose of nalmefene that is sufficient to produce aneffective response (i.e., a biological or medical response of a tissue,system, animal or human sought by a researcher, veterinarian, medicaldoctor or other clinician) upon administration to a patient. The“therapeutically effective amount” may vary depending on, inter alia,the disease and its severity, and on the age, weight, physical conditionand responsiveness of the patient to be treated. Furthermore, the“therapeutically effective amount” may vary if nalmefene is combinedwith one or more other pharmacologically active compounds; in such acase the amount of nalmefene might be lower, such as a sub-effectiveamount. In one embodiment, a “therapeutically effective amount” ofnalmefene is 18 mg calculated as the free base form.

In the present context, “treatment” and “treating” refers to themanagement and care of a patient for the purpose of combating acondition, such as a disease or a disorder. The term is intended toinclude the full spectrum of treatments for a given condition from whichthe patient is suffering, such as administration of the active compoundto alleviate the symptoms or complications, to delay the progression ofthe disease, disorder or condition, to alleviate or relief the symptomsand complications, and/or to cure or eliminate the disease, disorder orcondition as well as to prevent the condition, wherein prevention is tobe understood as the management and care of a patient for the purpose ofcombating the disease, condition, or disorder and includes theadministration of the active compounds to prevent the onset of thesymptoms or complications. In one aspect of the present invention,“treatment” and “treating” refers to prophylactic (preventive)treatment. In another aspect, “treatment” and “treating” refers to(curative) treatment. The patient to be treated is preferably a mammal,in particular a human being.

The term “alcohol dependence” is a commonly known term for a skilledperson and is described in the revised 4^(th) edition of the Diagnosticand Statistical Manual of Mental Disorders (DSM-IV-TR) (Diagnostic andStatistical Manual of Mental Disorders, 4^(th) edition text revision,American Psychiatric Publishing, 2000). As used herein, the term“alcohol dependence” is defined as the presence of three or more of theseven areas of life impairment related to alcohol in the same 12-monthperiod. These impairments include 1) tolerance, 2) withdrawal, 3) thealcohol is often taken in larger amounts or over a longer period thanwas intended, 4) persistent desire or unsuccessful efforts to cut downor control alcohol intake, 5) a great deal of time is spent inactivities necessary to obtain alcohol, intake alcohol, or recover fromits effects, 6) important social, occupational, or recreationalactivities are given up or reduced because of alcohol consumption, 7)alcohol use is continued despite knowledge of having a persistent orrecurrent physical or psychological problem that is likely to have beencaused or exacerbated by alcohol consumption.

DETAILED DESCRIPTION OF THE INVENTION

The inventor has surprisingly found that certain salts of nalmefene donot form hydrates when precipitated from water and/or said salts do notform solvates when precipitated from organic solvents, such as e.g.EtOH, MeOH, IPA, EtOAc, acetone, ACN, THF, MIBK, toluene and2,2,2-trifluoroethanol.

The non-hydrate forming nalmefene salts of the present invention havethe advantages that they are easy to work with, both from theperspective of chemical production and pharmaceutical production andstorage. For example, certain pharmaceutical processes such asgranulation by high shear mixing or fluid bed processing implies thatthe nalmefene salt will be partly or fully dissolved in the granulationliquid. This would, if the nalmefene salt is hydrate forming induce arisk of converting the salt into a hydrated form. Furthermore, thesubsequent drying of a granulate implies the risk that a hydrated saltform would lose water and be converted into a less hydrated form. Suchchanges imply that the stoichiometry can be changed during processingwhich have certain drawbacks such as the risk of obtaining an endproduct not fulfilling the specifications.

Pharmaceutical processes implying the risk of either hydrate formationor loss of water from a hydrate are e.g. wet granulation; fluid bedprocessing; drying at elevated temperature such as at a temperature inthe range of 60-90° C.; aqueous based spray drying; aqueous basedcoating of granules, pellets or tablets; milling at elevatedtemperature, such as at a temperature in the range of 60-150° C. Anon-hydrate forming salt of nalmefene would leave the pharmaceuticalprocessing of the compound with a higher degree of freedom, i.e. leavemore options to design the best possible process for the compound.

Also in chemical processing, avoidance of hydrate forming salts could beadvantageous from a process point of view as it enables the use of wateras a solvent in the purification process and also as a solvent forprecipitation without the risk of hydrate formation.

In terms of hydrate formation, the following salts of nalmefene havebeen shown not to form hydrates when precipitated from pure water atroom temperature and atmospheric pressure; the hydrogen adipate salt,the hydrogen malonate salt, the hydrogen fumarate salt, the hydrogensuccinate salt, the benzene sulfonate salt, the hydrogen maleate saltand the salicylate salt. This was unexpected, since it is known fromliterature (Brittain, H. G., Analytical Profiles of Drug Substances andExcipients; 1996, Vol. 24: 351-395 and WO 2010/063292) that the HCl saltof nalmefene, the only previously known salt of nalmefene, is onlythermodynamically stable in hydrated or solvated form. Further detailsregarding attempts to form hydrates from nalmefene salts are describedin Example 6.

The non-hydrate forming nalmefene salts of the present invention arefurther characterized by being anhydrous and stable on storage at 40°C./75% RH for at least one week. It is noted that the non-hydrateforming nalmefene salts of the present invention are not hygroscopic;they all absorb less than 1% of water at 90% RH which is reflected byDVS experiments in Example 5, Table 3.

The non-solvate forming nalmefene salts of the present invention impliesthe advantage in relation to the chemical processing that the lack ofsolvate formation makes it possible to select the optimal organicsolvent for the crystallization process and thereby optimize thepurification and yield. It is known from literature (Brittain, H. G.,Analytical Profiles of Drug Substances and Excipients; 1996, Vol. 24:351-395), that nalmefene hydrochloride form solvate when precipitatedfrom ethanol.

Solvate formation of the salts of the present invention was assessed inthe following solvents: EtOH, MeOH, IPA, EtOAc, acetone, ACN, THF, MIBK,toluene and 2,2,2-trifluoroethanol. No solvates were formed from thefollowing salts when precipitated from various organic solvents at roomtemperature and atmospheric pressure: the hydrogen adipate salt, theL-lactate salt and the hydrogen maleate salt. The hydrogen malonate saltformed solvate when precipitated from MeOH, the benzene sulfonate saltformed solvate when precipitated from EtOH and THF, and the salicylatesalt when precipitated from IPA. Furthermore, it was shown that thehydrogen fumarate and hydrogen succinate salts formed solvate when thesewere precipitated from 2,2,2-trifluoroethanol (which however, is not astandard solvent commonly used in chemical processes). Even thoughcertain salts of the present invention do form a solvate whenprecipitated from one particular organic solvent, said salts are notgenerally prone to solvate formation as they can be precipitated fromvarious other organic solvents without solvate formation. Forcomparison, it was shown that the hydrochloride salt formed solvate fromall the solvents. Further details regarding solvate formation fromnalmefene salts are described in Example 7.

Certain salts of the present invention possess additional advantages interms of aqueous solubility. The aqueous solubility of the salicylatesalt is 3 mg base/mL, the aqueous solubility of the hydrogen fumaratesalt, the hydrogen maleate salt and the benzene sulfonate salt is in therange of 27-29 mg base/mL, and the aqueous solubility of the hydrogenadipate salt is 65 mg base/mL (see table 4). Thereby, these five saltspossess an aqueous solubility that is considerably lower than theaqueous solubility of the known hydrochloride salt of nalmefene which is109 mg base/mL (unpublished data). This implies the advantages ofobtaining a better recovery of the compound from recrystallization froman aqueous solution and furthermore, a salt with low aqueous solubilitymay facilitate removal of certain impurities with higher solubility.

The aqueous solubility of an active ingredient is also of significancefor the choice of dosage form as it may have a direct impact on theformulation of certain dosage forms. Some patients, e.g. elderlypatients may have difficulties swallowing tablets, and oral dropsolutions may be a suitable alternative avoiding the need for swallowingtablets. In order to limit the volume of an oral drop solution, it isnecessary to have a high concentration of the active ingredient in thesolution, which again requires a high solubility of the compound. Theaqueous solubility of the lactate and the hydrogen succinate salts ofnalmefene were found to be 439 and 424 mg base/mL, respectively (Table4), which is considerably higher than the aqueous solubility of theknown hydrochloride salt of nalmefene which is 109 mg base/mL.

In brief, the nalmefene salts of the present invention can be preparedby the following general method. Nalmefene base is added an equivalentamount of the corresponding acid (e.g. adipic acid, malonic acid,L-lactic acid, fumaric acid, succinic acid, benzene sulfonic acid,maleic acid and salicylic acid, respectively) in an appropriate solventsuch as IPAc (isopropyl acetate) or EtOH. The suspension is heated to atleast 60° C. and subsequently cooled slowly to room temperature. Theprecipitated salt is isolated and optionally recrystallized in anappropriate solvent such as IPA (Isopropanol). Further details regardingpreparation of the salts of the invention are described in Examples 1and 2.

The nalmefene salts according to the present invention may be used inthe preparation of pharmaceutical compositions. Said pharmaceuticalcompositions may further comprise at least one pharmaceuticallyacceptable excipient, carrier and/or diluent, and may be in a soliddosage form, such as a tablet, for oral administration. In oneembodiment, the invention relates to such pharmaceutical composition.

Methods for the preparation of solid pharmaceutical preparations arewell known in the art. See, e.g., Remington: The Science and Practice ofPharmacy, 21st ed., Lippincott Williams & Wilkins (2005). Solidpreparations, such as tablets, may be prepared by mixing the activeingredients with an ordinary carrier, such as an adjuvant and/ordiluent, and subsequently compressing the mixture in a tabletingmachine. Non-limiting examples of adjuvants and/or diluents include:corn starch, lactose, talcum, magnesium stearate, gelatine, lactose,gums, and the like. Any other appropriate adjuvant or additive such ascolorings, aroma, and preservatives may also be used provided that theyare compatible with the active ingredients. The pharmaceuticalcompositions of the invention thus typically comprise an effectiveamount of a salt of the present invention and one or morepharmaceutically acceptable carriers.

The nalmefene salts of the present invention may be administered in anysuitable way, e.g. orally or parenterally, and they may be presented inany suitable form for such administration, e.g., in the form of tablets,capsules, powders, syrups, oral drop solutions or in the form ofsolutions or dispersions for injection. In one embodiment, thepharmaceutical composition will comprise a nalmefene salt of the presentinvention in a therapeutically effective amount.

Preferably, the amount of a nalmefene salt of the present invention in apharmaceutical composition in unit dosage form is from about 10 mg toabout 100 mg, such as from about 10 mg to about 60 mg, e.g. from about10 mg to about 40 mg, or about 20 mg. In one embodiment, the amount of analmefene salt of the present invention in a pharmaceutical compositionin unit dosage form corresponds to 18 mg of nalmefene free base.

In particular, it is envisaged that a pharmaceutical compositioncomprising a nalmefene salt of the present invention may be used forreduction of alcohol consumption in patients with alcohol dependence. Inanother embodiment, a composition comprising a nalmefene salt of thepresent invention may be used for the manufacture of a medicament forreduction of alcohol consumption in patients with alcohol dependence. Inanother embodiment, the invention relates to a method for treatingalcohol dependence, comprising administering a therapeutically effectiveamount of a nalmefene salt of the present invention to a patient in theneed thereof.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference in theirentirety and to the same extent as if each reference were individuallyand specifically indicated to be incorporated by reference and were setforth in its entirety herein (to the maximum extent permitted by law),regardless of any separately provided incorporation of particulardocuments made elsewhere herein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context. For example, the phrase “the compound”is to be understood as referring to various “compounds” of the inventionor particular described aspect, unless otherwise indicated.

The description herein of any aspect or aspect of the invention usingterms such as “comprising”, “having,” “including,” or “containing” withreference to an element or elements is intended to provide support for asimilar aspect or aspect of the invention that “consists of”, “consistsessentially of”, or “substantially comprises” that particular element orelements, unless otherwise stated or clearly contradicted by context(e.g., a composition described herein as comprising a particular elementshould be understood as also describing a composition consisting of thatelement, unless otherwise stated or clearly contradicted by context).

It should be understood that the various aspects, embodiments,implementations and features of the invention mentioned herein may beclaimed separately, or in any combination.

Embodiments According to the Invention

In the following, embodiments of the invention are disclosed. The firstembodiment is denoted E1, the second embodiment is denoted E2 and soforth.

-   E1. A salt of the compound of formula [I]

wherein said salt falls within at least one of the two followingcategories:

a) non-hydrate forming salt;

b) non-solvate forming salt.

-   E2. The salt according to embodiment 1, which salt is in a solid    form.-   E3. The salt according to any of embodiments 1-2 which salt is    crystalline.-   E4. The salt according to any of embodiments 1-3, which salt is    selected from the hydrogen adipate salt, the hydrogen malonate salt,    the lactate salt, the hydrogen fumarate salt, the hydrogen succinate    salt, the benzene sulfonate salt, the hydrogen maleate salt and the    salicylate salt of the compound of formula [I].-   E5. The salt according to any of embodiments 1-3, wherein said salt    is a non-hydrate forming salt.-   E6. The salt according to embodiment 5, wherein there is less than    30 mol % water present in the crystal lattice of said salt.-   E7. The salt according to embodiment 6, wherein there is less than    25 mol % water, such as less than 20 mol % water, such as less than    15 mol % water, such as less than 10 mol % water, such as less than    5 mol % water, such as less than 4, 3, 2 or 1 mol % water present in    the crystal lattice of said salt.-   E8. The salt according to any of embodiments 5-7, wherein there is    substantially no water present in the crystal lattice of said salt.-   E9. The salt according to any of embodiments 5-8, which salt is    selected from the hydrogen adipate salt, the hydrogen malonate salt,    the hydrogen fumarate salt and the hydrogen succinate salt, the    benzene sulfonate salt, the hydrogen maleate salt and the salicylate    salt of the compound of formula [I].-   E10. The salt according to any of embodiments 1-3, wherein said salt    is a non-solvate forming salt.-   E11. The salt according to embodiment 10, which salt does not form    solvate when precipitated from any of the solvents selected from    EtOH, MeOH, IPA, EtOAc, acetone, ACN, THF, MIBK, toluene and    2,2,2-trifluoroethanol.-   E12. The salt according to any of embodiments 10-11, which salt is    selected from the hydrogen adipate salt, the lactate salt and the    hydrogen maleate salt of the compound of formula [I].-   E13. The salt according to any of embodiments 1-3, which salt when    precipitated from one of the solvents selected from EtOH, MeOH, IPA,    EtOAc, acetone, ACN, THF, MIBK, toluene and 2,2,2-trifluoroethanol,    does only form solvate from one or two of said solvents.-   E14. The salt according to embodiment 13, which salt is selected    from the hydrogen malonate salt, the hydrogen fumarate salt, the    hydrogen succinate salt, the benzene sulfonate salt and the    salicylate salt of nalmefene.-   E15. The salt according to any of embodiments 11 or 13, which salt    does not form solvate when precipitated from any of the solvents    selected from EtOH, IPA, EtOAc, acetone, ACN, THF, MIBK, toluene and    2,2,2-trifluoroethanol.-   E16. The salt according to embodiment 15, which salt is selected    from the hydrogen adipate salt, the lactate salt, the hydrogen    maleate salt and the hydrogen malonate salt of the compound of    formula [I].-   E17. The salt according to any of embodiments 11 or 13, which salt    does not form solvate when precipitated from any of the solvents    selected from EtOH, MeOH, IPA, EtOAc, acetone, ACN, THF, MIBK and    toluene.-   E18. The salt according to embodiment 17, which salt is selected    from the hydrogen adipate salt, the lactate salt, the hydrogen    maleate salt, the hydrogen fumarate salt and the hydrogen succinate    salt of the compound of formula [I].-   E19. The salt according to any of embodiments 11 or 13, which salt    does not form solvate when precipitated from any of the solvents    selected from MeOH, IPA, EtOAc, acetone, ACN, MIBK, toluene and    2,2,2-trifluoroethanol.-   E20. The salt according to embodiment 19, which salt is selected    from the hydrogen adipate salt, the lactate salt, the hydrogen    maleate salt, and the benzene sulfonate salt of the compound of    formula [I].-   E21. The salt according to any of embodiments 11 or 13, which salt    does not form solvate when precipitated from any of the solvents    selected from EtOH, MeOH, EtOAc, acetone, ACN, THF, MIBK, toluene    and 2,2,2-trifluoroethanol.-   E22. The salt according to embodiment 21, which salt is selected    from the hydrogen adipate salt, the lactate salt, the hydrogen    maleate salt, and the salicylate salt of the compound of formula    [I].-   E23. The salt according to any of embodiments 1-8 and 10-11, wherein    said salt is both a non-hydrate forming salt and a non-solvate    forming salt.-   E24. The salt according to any of embodiments 1-12 and 15-23, which    salt is the hydrogen adipate salt of the compound of formula [I].-   E25. The salt according to embodiment 24, which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 7.66, 11.40, 12.92,    14.90, 15.63, 16.21, 18.22, 18.64, 20.48 and 21.18°.-   E26. The salt according to embodiment 25, which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 7.66, 11.40, 12.92,    14.90 and 16.21°.-   E27. The salt according to any of embodiments 24-26, which crystal    form is characterized by an XRPD obtained using CuK_(α1) radiation    (λ=1.5406 Å) as depicted in FIG. 1.-   E28. The salt according to any of embodiments 24-27, which crystal    form is characterized by having a DSC trace showing an endotherm    with onset about 179° C.-   E29. The salt according to any of embodiments 1-9 and 13-16 which    salt is the hydrogen malonate salt of the compound of formula [I].-   E30. The salt according to embodiment 29, which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 10.48, 10.74, 11.31,    11.92, 12.14, 14.40, 15.43, 15.61, 16.63 and 21.03°.-   E31. The salt according to embodiment 30, which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 10.48, 10.74, 11.31,    11.92 and 12.14°.-   E32. The salt according to any of embodiments 29-31, which crystal    form is characterized by an XRPD obtained using CuK_(α1) radiation    (λ=1.5406 Å) as depicted in FIG. 2.-   E33. The salt according to any of embodiments 29-32, which crystal    form is characterized by having a DSC trace showing an endotherm    with onset about 191° C. (degradation).-   E34. The salt according to any of embodiments 1-4, 10-12 and 15-22,    which salt is the lactate salt of the compound of formula [I].-   E35. The salt according to embodiment 34, which salt is the    DL-lactate salt of the compound of formula [I].-   E36. The salt according to embodiment 34, which salt is the    D-lactate salt of the compound of formula [I].-   E37. The salt according to embodiment 34, which salt is the    L-lactate salt of the compound of formula [I].-   E38. The salt according to embodiment 37, which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 10.41, 11.16, 11.80,    12.46, 15.23, 15.85, 16.64, 19.23, 19.71 and 20.11°.-   E39. The salt according to embodiment 38, which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 10.41, 11.16, 11.80,    12.46 and 15.85°.-   E40. The salt according to any of embodiments 37-39, which crystal    form is characterized by an XRPD obtained using CuK_(α1) radiation    (λ=1.5406 Å) as depicted in FIG. 3.-   E41. The salt according to any of embodiments 37-40, which crystal    form is characterized by having a DSC trace showing an endotherm    with onset about 183° C. (degradation).-   E42. The salt according to any of embodiments 1-9, 13-14 and 17-18,    which salt is the hydrogen fumarate salt of the compound of formula    [I].-   E43. The salt according to embodiment 42, which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 8.00, 10.90, 13.04,    13.70, 14.90, 16.95, 17.68, 18.34, 18.85 and 20.77°.-   E44. The salt according to embodiment 43, which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 8.00, 10.90, 13.04,    13.70 and 14.90°.-   E45. The salt according to any of embodiments 42-44, which crystal    form is characterized by an XRPD obtained using CuK_(α1) radiation    (λ=1.5406 Å) as depicted in FIG. 4.-   E46. The salt according to any of embodiments 42-45, which crystal    form is characterized by having a DSC trace showing an endotherm    with onset about 254° C. (degradation).-   E47. The salt according to any of embodiments 1-9, 13-14 and 17-18,    which salt is the hydrogen succinate salt of the compound of formula    [I].-   E48. The salt according to embodiment 47, which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 8.03, 10.72, 10.90,    11.52, 13.00, 13.70, 14.79, 16.86, 17.72 and 18.26°.-   E49. The salt according to embodiment 48, which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 8.03, 10.90, 13.00,    13.70 and 14.79°.-   E50. The salt according to any of embodiments 47-49, which crystal    form is characterized by an XRPD obtained using CuK_(α1) radiation    (λ=1.5406 Å) as depicted in FIG. 5.-   E51. The salt according to any of embodiments 47-50, which crystal    form is characterized by having a DSC trace showing an endotherm    with onset about 188° C.-   E52. The salt according to any of embodiments 1-9, 13-14 and 19-20,    which salt is the benzene sulfonate salt of the compound of formula    [I].-   E53. The salt according to embodiment 52, which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 7.07, 10.77, 13.42,    13.62, 14.98, 16.34, 17.06, 17.79, 19.64 and 20.39°.-   E54. The salt according to embodiment 53 which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 1.07, 10.77, 13.42,    13.62, 14.98 and 16.34°.-   E55. The salt according to any of embodiments 52-54, which crystal    form is characterized by an XRPD obtained using CuK_(α1) radiation    (λ=1.5406 Å) as depicted in FIG. 6.-   E56. The salt according to any of embodiments 52-55, which crystal    form is characterized by having a DSC trace showing an endotherm    with onset about 222° C.-   E57. The salt according to any of embodiments 1-12 and 15-23, which    salt is the hydrogen maleate salt of the compound of formula [I].-   E58 The salt according to embodiment 57, which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 7.64, 10.59, 11.03,    11.81, 12.94, 14.92, 15.32, 15.92, 16.13 and 16.86°.-   E59. The salt according to embodiment 58 which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 7.64, 10.59, 12.94,    14.92 and 15.32°.-   E60. The salt according to any of embodiments 57-59, which crystal    form is characterized by an XRPD obtained using CuK_(α1) radiation    (λ=1.5406 Å) as depicted in FIG. 7.-   E61. The salt according to any of embodiments 57-60, which crystal    form is characterized by having a DSC trace showing an endotherm    with onset about 213° C. (degradation).-   E62. The salt according to any of embodiments 1-9, 13-14 and 21-22,    which salt is the salicylate salt of the compound of formula [I].-   E63. The salt according to embodiment 62, which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 8.44, 9.78, 11.08,    12.16, 13.21, 14.40, 16.24, 16.71, 17.43 and 19.62°.-   E64. The salt according to embodiment 63 which crystal form is    characterized by an XRPD obtained using CuK_(α1) radiation (λ=1.5406    Å) showing peaks at the following 2θ-angles: 8.44, 9.78, 11.08,    12.16 and 13.21°.-   E65. The salt according to any of embodiments 62-64, which crystal    form is characterized by an XRPD obtained using CuK_(α1) radiation    (λ=1.5406 Å) as depicted in FIG. 8.-   E66. The salt according to any of embodiments 62-65, which crystal    form is characterized by having a DSC trace showing an endotherm    with onset about 196° C.-   E67. A pharmaceutical composition comprising a salt according to any    of embodiments 1-66.-   E68. The pharmaceutical composition according to embodiment 67,    characterized in that said composition are manufactured by a process    comprising one or more of the process steps selected from wet    granulation, fluid bed processing, drying at elevated temperature    such as at a temperature above room temperature, aqueous based spray    drying, aqueous based coating of granules, pellets or tablets,    milling at elevated temperature.-   E69. A salt according to any of embodiments 1-66 for use as a    medicament.-   E70. A salt according to any of embodiments 1-66 for use in therapy.-   E71. A salt according to any of embodiments 1-66 or a pharmaceutical    composition according to any embodiments 67-68 for use reduction of    alcohol consumption in a patient with alcohol dependence.-   E72. A method for the reduction of alcohol consumption in a patient    with alcohol dependence, which method comprises the administration    of a therapeutically effective amount of a salt according to any of    embodiments 1-66 to said patient.

EXAMPLES

The invention will be illustrated by the following non-limitingexamples.

Example 1 Preparation of the Hydrogen Adipate Salt, the HydrogenMalonate Salt, the Lactate Salt, the Hydrogen Fumarate Salt and theHydrogen Succinate Salt of Nalmefene

To nalmefene base (5.5 g) was added one molar equivalent of thecorresponding acid (adipic acid, malonic acid, L-lactic acid, fumaricacid or succinic acid, respectively) in IPAc (125 mL isopropyl acetate).The suspension was heated to at least 60° C. (not completely dissolved)and subsequently allowed to cool slowly to room temperature.

The first batch of the nalmefene hydrogen malonate salt contained anexcess of the free base, and the first batch of the nalmefene hydrogenfumarate salt contained excess of fumaric acid as seen by XRPD. Thesetwo batches were then recrystallized in IPA.

Example 2 Preparation of the Benzene Sulfonate Salt, the HydrogenMaleate Salt and the Salicylate Salt of Nalmefene

Benzene sulfonate: A mixture of nalmefene free base (5.0 g) and onemolar equivalent of benzene sulfonic acid in 25 mL EtOH was heated toreflux whereby all dissolved. The mixture was allowed to cool slowly toroom temperature. As no precipitation occurred after 1 h, seed materialwas obtained by adding a few drops of IPAc to in total 1 mL of thesolution in a small tube. This gave a precipitate, which was then addedto reaction mixture, leading to subsequent crystallization. The mixturewas stirred at room temperature for 2-3 h. The resulting salt wasisolated by filtration and washed with a small amount of ethanol anddried under vacuum at 50° C. overnight. The resulting salt was asolvate. This was subsequently suspended in water with stirring for afew hours, and subsequently filtered and dried under vacuum. Thisprecipitate was found to be solvent free.

Maleate and salicylate: A mixture of nalmefene free base (5.0 g) and onemolar equivalent of the corresponding acid (maleic acid or salicylicacid) in isopropyl acetate (50 mL) was heated to reflux and then allowedto cool slowly to room temperature. Precipitation occurred, and themixture was stirred at room temperature for 2-3 h. The precipitate wasisolated by filtration, washed with a small amount of isopropyl acetateand dried under vacuum at 50° C. overnight. The hydrogen maleate saltshowed some extra reflections in the XRPD and extra endotherms in DSC.After being slurried in water (for determination of the solubility inwater) these extra reflections/endotherms disappeared.

Example 3 XRPD Characterization

X-Ray powder diffractograms were measured on a PANalytical X'Pert PROX-Ray Diffractometer using CuK_(α1) radiation. The samples were measuredin reflection mode in the 2θ-range 2-40° using an X'celerator detector.XRPD patterns of the hydrogen adipate, hydrogen malonate, L-lactate,hydrogen fumarate, hydrogen succinate, benzene sulfonate, hydrogenmaleate and salicylate salts are shown in FIGS. 1-8 and characteristicmain peaks are listed in Table 1 below.

TABLE 1 Characteristic XRPDs on salts of nalmefene, obtained usingCuK_(α1) radiation (λ = 1.5406 Å) showing peaks at the following2θ-angles Characteristic main peaks Salt (expressed in degree ofdiffraction angle 2θ) Hydrogen adipate 7.66, 11.40, 12.92, 14.90, 15.63,16.21, 18.22, 18.64, 20.48, 21.18 Hydrogen malonate 10.48, 10.74, 11.31,11.92, 12.14, 14.40, 15.43, 15.61, 16.63, 21.03 L-lactate 10.41, 11.16,11.80, 12.46, 15.23, 15.85, 16.64, 19.23, 19.71, 20.11 Hydrogen Fumarate8.00, 10.90, 13.04, 13.70, 14.90, 16.95, 17.68, 18.34, 18.85, 20.77Hydrogen succinate 8.03, 10.72, 10.90, 11.52, 13.00, 13.70, 14.79,16.86, 17.72, 18.26 Benzene sulfonate 7.07, 10.77, 13.42, 13.62, 14.98,16.34, 17.06, 17.79, 19.64, 20.39 Hydrogen maleate 7.64, 10.59, 11.03,11.81, 12.94, 14.92, 15.32, 15.92, 16.13, 16.86 Salicylate 8.44, 9.78,11.08, 12.16, 13.21, 14.40, 16.24, 16.71, 17.43, 19.62

Example 4 Thermal Analysis

The Differential Scanning Calorimetry (DSC) measurements are performedusing equipment TA-Instruments DSC-Q2000 calibrated at 5°/min to givethe melting point as onset value. About 2 mg of sample is heated 5°/minunder nitrogen flow in a closed pan with a pinhole in the lid.

Thermo gravimetric analysis (TGA) is performed using a TA-instrumentsTGA-Q500. 1-10 mg sample is heated 10°/min in an open pan under nitrogenflow.

TGA and DSC thermograms of the hydrogen adipate, hydrogen malonate,L-lactate, hydrogen fumarate, hydrogen succinate, benzene sulfonate,hydrogen maleate and salicylate salts are shown in FIGS. 9-16 and DSCdata are shown in Table 2 below.

TABLE 2 DSC data of salts of nalmefene DSC endo- DSC endo- therm onsettherm peak dH Salt (° C.) (° C.) (J/g) Hydrogen adipate 179.4 179.8 124Hydrogen malonate 191.1 191.5 256 L-lactate 182.5 187.4 72 HydrogenFumarate 254.0 254.4 157 Hydrogen succinate 188.4 188.4 108 Benzenesulfonate 222.0 223.0 75 Hydrogen maleate 213.4 215.7 167 Salicylate195.6 196.2 107

Example 5 DVS Experiments

Dynamic vapour sorption experiments were performed using a SMS DVSadvantage 01 changing the relative humidity from 30-40% RH up to 90-95%RH in steps of 10% RH. Data are shown in Table 3 below.

TABLE 3 Water absorption at 90% RH determined by DVS. Salt % abs. at 90%RH Hydrogen adipate 0.35% Hydrogen malonate 0.35% L-lactate 1.2%Hydrogen Fumarate 0.6% Hydrogen succinate <0.1% Benzene sulfonate <0.2%Hydrogen maleate 0.2% Salicylate 0.4%

Example 6 Determination of Aqueous Solubility and Attempt to FormHydrates

Thermodynamic solubility of the hydrogen adipate, hydrogen malonate,L-lactate, hydrogen fumarate, hydrogen succinate, benzene sulfonate,hydrogen maleate and salicylate salts was measured by shaking an excessamount of the eight nalmefene salts in pure water in a sealed containerat a constant temperature at room temperature (23° C.±2°). Afterequilibrium was attained, a sample was withdrawn, the solid filtered orcentrifuged off, and the clear filtrate/supernatant was diluted andassayed by HPLC. The experiments with hydrogen succinate and L-lactateled to complete dissolution in the first determination. These solutionswere left for evaporation of the water leading to an oil. Theseexperiments were subsequently repeated using a larger amount of solid.Except for L-lactate all precipitates were the same as the initialcompound, thus no hydrates were formed. The L-lactate led to aprecipitate with a different XRPD than the initial compound and TGAshowed a weight loss of 4.0% up to 135° C. which corresponds to amonohydrate.

Aqueous solubility of the nalmefene salts are listed in Table 4. Allsolubilities are normalised to the relative solubility of nalmefene freebase.

TABLE 4 Aqueous solubility of salts of nalmefene at 23° C. ± 2°Solubility Salt pH (mg base/mL) Hydrogen adipate 4.72 65 Hydrogenmalonate 4.08 130 L-lactate 5.64 439 Hydrogen Fumarate 3.49 27 Hydrogensuccinate 4.61 424 Benzene sulfonate 3.12 28 Hydrogen maleate 5.93 29Salicylate 7.14 3.0

Example 7 Determination of Solubility in Organic Solvents and Attempt toForm Solvates

The solubility of the hydrogen adipate, hydrogen malonate, L-lactate,hydrogen fumarate and hydrogen succinate, benzene sulfonate, hydrogenmaleate and salicylate salts was determined in the following organicsolvents: EtOH, MeOH, IPA, EtOAc, acetone, ACN, THF, MIBK, toluene and2,2,2-trifluoroethanol. The suspensions were heated with the purpose ofobtaining complete dissolution and then cooled to room temperature andleft for equilibrium to be attained. The clear supernatant was dilutedand assayed by HPLC. All precipitates were analyzed by XRPD. Except forhydrogen malonate in MeOH, benzene sulfonate in EtOH and THF, hydrogenfumarate and hydrogen succinate in 2,2,2-trifluoroethanol and salicylatein IPA, all precipitates were the same crystal form as the initialmaterial, thus no solvates were formed.

For comparison, the solvate formation from nalmefene hydrochloride wasalso investigated. It was shown that the hydrochloride salt formedsolvate from all the organic solvents (EtOH, MeOH, IPA, EtOAc, acetone,ACN, THF, MIBK, toluene and 2,2,2-trifluoroethanol). Solubilities of thenalmefene salts in organic solvents are listed in Table 5. Allsolubilities are normalised to the relative solubility of nalmefene freebase.

TABLE 5 Solubility of salts of nalmefene in organic solvents at 23° C. ±2° (mg base/mL) Salt EtOH MeOH IPA EtOAc acetone ACN Hydrogen adipate 27143 8.3 2.1 6.0 1.85 Hydrogen malonate 26  167* 11 0.7 2.7 10 L-lactate143  299 31 5.3 11.9 9.2 Hydrogen Fumarate 16  73 2.5 3.6 0.67 0.22Hydrogen succinate 51 237 11 1.6 6.84 4.7 Benzene sulfonate  13* 152 3.10.14 2.5 26 Hydrogen maleate 48 121 3.4 0.55 3.7 12 Salicylate 19  910.5* 2.0 9.7 8.2 Salt THF MIBK toluene 2,2,2-trifluoro-EtOH Hydrogenadipate 65 2.6 0.21 236 Hydrogen malonate 4.9 0.73 0.13 325 L-lactate44.5 5.2 0.43 >370   Hydrogen Fumarate 6.6 0.1 0.01  24* Hydrogensuccinate 29 1.6 0.13  154* Benzene sulfonate 0.35 0.19 n.a. 314Hydrogen maleate 2.1 0.64 n.a. 248 Salicylate 35 2.9 n.a. 120*precipitated as solvate n.a.: not available, n.d.: not detected

HPLC analysis of solubility samples according to Examples 6 and 7 wasperformed on an X-bridge C-18 column using 25 mM phosphate buffer pH6.0/MeOH 50/50 as mobile phase and UV detection at 230 nm.

The invention claimed is:
 1. A salt of the compound of formula [I]

wherein said salt is crystalline and wherein said salt falls within atleast one of the two following categories: (a) a salt wherein watermolecules do not form part of the crystal lattice of said salt when saidsalt is precipitated from water at atmospheric pressure and in atemperature range between 15-30° C.; and (b) a salt wherein solventmolecules do not form part of the crystal lattice of said salt when saidsalt is precipitated from a solvent selected from the group consistingof: EtOH, MeOH, IPA, EtOAc, acetone, ACN, THF, MIBK, toluene and2,2,2-trifluoroethanol, at atmospheric pressure and in a temperaturerange between 15-30° C.
 2. The salt according to claim 1, wherein saidsalt is selected from the group consisting of: the hydrogen adipatesalt, the hydrogen malonate salt, the lactate salt, the hydrogenfumarate salt, the hydrogen succinate salt, the benzene sulfonate salt,the hydrogen maleate salt and the salicylate salt of the compound offormula [I].
 3. The salt according to claim 1, wherein said salt fallsat least within category (a).
 4. The salt according to claim 3, of whichsalt any isolated crystal form contains less than 30 mol % water in thecrystal lattice of said salt.
 5. The salt according to claim 4, of whichsalt any isolated crystal form contains less than 25 mol % water presentin the crystal lattice of said salt.
 6. The salt according to claim 1,wherein said salt falls at least within category (b).
 7. The saltaccording to claim 6, wherein when said salt is precipitated from asolvent selected from said group at least one of said formed crystallattices does not include solvent.
 8. The salt according to claim 1,wherein said salt falls within both category (a) and category (b).
 9. Apharmaceutical composition comprising the salt according to claim
 1. 10.The pharmaceutical composition according to claim 9, wherein saidcomposition is manufactured by a process comprising one or more processsteps selected from the group consisting of: (1) wet granulation, (2)fluid bed processing, (3) drying at elevated temperature, (4) aqueousbased spray drying, (5) aqueous based coating of granules, pellets ortablets, and (6) milling at elevated temperature.
 11. A method oftreatment of alcohol dependence, wherein said method comprisesadministering the pharmaceutical composition of claim 9 to a subject inneed thereof.
 12. The method of treatment of claim 11, wherein saidsubject suffers from alcohol dependence and said treatment reducesalcohol consumption.
 13. The salt according to claim 1, wherein saidsalt falls within at least one of the two following categories: (a) asalt wherein water molecules do not form part of the crystal lattice ofsaid salt when said salt is precipitated from water at atmosphericpressure in a temperature range between 20-25° C.; and (b) a saltwherein solvent molecules do not form part of the crystal lattice ofsaid salt when said salt is precipitated from a solvent selected fromthe group consisting of: EtOH, MeOH, IPA, EtOAc, acetone, ACN, THF,MIBK, toluene and 2,2,2-trifluoroethanol, at atmospheric pressure and ina temperature range between 20-25° C.
 14. The salt according to claim 6,wherein when said salt is precipitated from a solvent selected from saidgroup none of said formed crystal lattices includes solvent.